Carboxylic acid therapeutic agents

ABSTRACT

A series of substituted phenylacetic acid compounds and their derivatives, including the pharmacologically acceptable base salts of said acids, have been found to be active as oral hypoglycemic agents. Preferred member compounds include 6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, chroman-4-carboxylic acid, p-chlorophenylacetic acid, o-methylphenylacetic acid, o-methoxyphenylacetic acid, p-methoxyphenylacetic acid and α,α-di(4-methoxyphenyl)acetic acid. Synthetic routes leading to those member compounds which are novel per se are described in some detail.

This is a division of application Ser. No. 199,153, filed on Oct. 21,1980 now U.S. Pat. No. 4,305,955.

BACKGROUND OF THE INVENTION

This invention relates to new and useful carboxylic acid hypoglycemicagents. More particularly, it is concerned with a series of substitutedphenylacetic acids and their derivatives, including the base salts ofsaid acids with pharmacologically acceptable cations, which are usefulin therapy as oral hypoglycemic agents for the treatment of diabetes.The invention also includes various novel oral pharmaceuticalcompositions as well as a method of therapy.

In the past, various attempts have been made by numerous investigatorsin the specialized field of synthetic organic medicinal chemistry toobtain new and better oral hypoglycemic agents. For the most part, theseefforts have principally involved the synthesis and testing of variousheretofore new and unavailable organic compounds, particularly in thearea of the sulfonylureas, in an endeavor to determine their ability tolower blood sugar (i.e., glucose) levels when given by the oral route ofadministration. However, in the search for new and still more effectiveantidiabetic agents, far less is known about the effect ofnonsulfonylureas and this is particularly so in the case of variouscarboxylic acid compounds. For instance, G. A. Stewart in Dtsch.-Eng.Med. Rundsch. (Anglo-German Medical Review), Vol. 1, p. 334 (1962)reports that phenylacetic acid is hypoglycemic in normal guinea pigswhen given by the oral route of administration at 500 and 750 mg./kg.,respectively, while S. Ch. Lahiri et al. in the Journal of the IndianChemical Society, Vol. 53, p. 1041 (1976) have additionally found that6-methoxyindan-1-carboxylic acid and 6-methoxyindan-1-acetic acid areboth hypoglycemic in normal and alloxan-diabetic rabbits when given bythe oral route of administration at dose levels in the neighborhood of200 mg./kg., respectively. However, none of these prior art compoundspossess any outstanding clinical (or even pharmacological) advantagesover that of either chlorpropamide or tolbutamide when used in thisconnection.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now been rathersurprisingly found that certain cyclic and non-cyclic phenylacetic acidsare extremely useful when employed as oral hypoglycemic agents for thetreatment of diabetic subjects despite the fact that they are employedat dose levels where the aforementioned prior art compounds exhibitlittle or no activity. More particularly, the novel oral pharmaceuticalcompositions of this invention all comprise a pharmaceuticallyacceptable carrier and an effective blood sugar lowering amount of anoral hypoglycemic agent, said agent being a compound selected from thegroup consisting of carboxylic acids of the formulae: ##STR1## and thelower alkyl esters and unsubstituted amide derivatives thereof, and thebase salts of said acids with pharmacologically acceptable cations,wherein W is --CH₂ -- or --CH(CH₃)--; X is hydrogen or lower alkyl; X¹is hydrogen, lower alkyl, lower alkoxy or lower phenylalkoxy, with theproviso that when X¹ is other that lower alkyl, X is hydrogen; X² isfluorine, chlorine, bromine, lower alkyl, lower alkoxy or lowerphenylalkoxy; and Y is oxygen or sulfur. These compounds are all usefulin lowering blood sugar levels when given by the oral route ofadministration, i.e., they are useful as oral hypoglycemic agents.

The novel compounds of this invention are those carboxylic acids offormula I where X is hydrogen and X¹ is other than hydrogen, methyl ormethoxy, and those of formula II where at least one of X and X¹ isalways other than hydrogen. Additionally, the carboxylic acids offormula IV are all novel compounds.

Accordingly, the novel compounds of formula I comprise1,2,3,4-tetrahydronaphthalenecarboxylic acids of the formula: ##STR2##and the lower alkyl esters and unsubstituted amide derivatives thereof,and the base salts of said acids with pharmacologically acceptablecations, wherein X³ is lower phenylalkoxy and W is --CH₂ -- or--CH(CH₃)--.

The novel compounds of formula II comprise chroman andthiochromancarboxylic acids of the formula: ##STR3## and the lower alkylesters and unsubstituted amide derivatives thereof, and the base saltsof said acids with pharmaceutically acceptable cations, wherein X⁴ islower alkoxy or lower phenylalkoxy and Y is oxygen or sulfur.

Lastly, the novel compounds of formula IV comprise α,α-diphenylaceticacids of the formula: ##STR4## and the lower alkyl esters andunsubstituted amide derivatives thereof, and the base salts of saidacids with pharmacologically acceptable cations, where X² is fluorine,chlorine, bromine, lower alkyl, lower alkoxy or lower phenylalkoxy.

Of especial interest in this connection are such typical and preferredmember compounds of the invention as4-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid,6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid,6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid,6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid,chroman-4-carboxylic acid, thiochroman-4-carboxylic acid,p-chlorophenylacetic acid, o-methylphenylacetic acid,o-methoxyphenylacetic acid, p-methoxyphenylacetic acid andα,α-di(4-methoxyphenyl)acetic acid, respectively. These particularcompounds are all highly potent as regards their hypoglycemic activity(i.e., they exhibit a marked improvement in glucose tolerance). Thepreferred 6-substituted-1,2,3,4-tetrahydronaphthalene-1-carboxylic acidswhere the 6-substituent is other than methoxy, as well asthiochroman-4-carboxylic acid and α,α-di(4-methoxyphenyl)acetic acidare, as previously indicated, new compounds per se.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the process employed for preparing the compounds ofthis invention of structural formulae I-II and IV as previously defined,an appropriately substituted ketone compound, such as the corresponding1-tetralone, 2-tetralone, 4-chromanone, thiochroman-4-one andsymmetrically disubstituted benzophenone, of the respective formulae:##STR5## wherein W, X, X¹, X² and Y are all as previously defined, istreated with a suitable trialkylsilyl cyanide to form the correspondingcyanotrialkylsilyloxy derivative, followed by reductive hydrolysis ofthe latter intermediate to yield the desired acid. A preferredtrialkylsilyl cyanide for use in this connection is trimethylsilylcyanide, although any lower trialkylsilyl cyanide having up to fourcarbon atoms in each alkyl moiety may be employed in the aforesaidaddition reaction. In general, this particular reaction is normallycarried out in the presence of a Lewis acid catalyst, such as a zinc oraluminum halide (like zinc iodide) or boron trifluoride, with zinciodide being the preferred catalyst for the present purposes at hand.Moreover, the reaction is conducted at a temperature that is in therange of from about 0° C. up to about 50° C. (with the preferredtemperature range being 0°-20° C.) either neat or in a reaction-inertorganic solvent, such as diethyl ether, dimethoxyethane,tetrahydrofuran, dioxane and the like, and it is usually conducted in aninert atmosphere, preferably one that is nitrogen. The cyanotrialkylsiloxy derivative so obtained is then converted to the desiredcarboxylic acid compound by simply treating said cyano ether with astannous halide salt, such as stannous chloride dihydrate, for example,in a concentrated acid mix such as a mixture of glacial acetic acid andconcentrated hydrochloric acid. The latter reaction (i.e., the reductivehydrolysis step) is usually conducted at a temperature that is in therange of from about 100° C. up to about 200° C. (and preferably at thereflux point) for a period of about 12 to 72 hours. Upon completion ofthe reaction, the desired product (i.e., the carboxylic acid finalproduct having the requisite structural formula) is easily isolated in aconventional manner and used as such or else simply converted to asuitable derivative thereof as will hereinafter be more fully described.

Needless to say, compounds of the invention of structural formula IIIcan also be prepared by using the hereinbefore described two-stepreaction process for synthesizing the cyclic and non-cyclic phenylaceticacid compounds, only this time employing an appropriately substitutedaldehyde compound as starting material in place of the correspondingketone substrate (see structural formula VIII). However, many of thecompounds of structural formula III are commercially available or elsecan be prepared by simpler routes well-known to those skilled in theart. On the other hand, certain compounds of the invention (ofstructural formulae I-IV) having a ring substituent (X¹, X²) which islower alkoxy of more than one carbon atom or lower phenylalkoxy arenovel per se and can alternatively be prepared from the correspondingmethoxy compounds by first converting same to the corresponding hydroxyderivatives and then alkylating the latter with the appropriate agent ofchoice (e.g., ethyl iodide or benzyl bromide, as the case may be) in amanner well known to those skilled in the art. As previously indicated,all these acid compounds (of structural formula III and so on) can beused as such for the present purposes at hand or else simply convertedto the corresponding lower alkyl ester and unsubstituted amidederivatives thereof in accordance with conventional techniques.

The lower alkyl esters of the non-aromatic carboxylic acids of thisinvention are generally prepared by condensation of the acid with theappropriate alcohol of choice in the presence of an acid catalyst inaccordance with conventional organic procedure. The unsubstituted amidederivatives, on the other hand, are readily prepared by using standardprocedures, for example, by treating the corresponding acid chloridewith ammonia under basic conditions and thereafter isolating the amidefinal product in the usual manner.

The ketone starting materials (of structural formulae V-VIII) requiredfor preparing the carboxylic acid compounds of this invention are, forthe most part, known compounds and are either readily availablecommercially, like 1-tetralone, 4-methyl-1-tetralone,5-methoxy-1-tetralone, 6-methoxy-1-tetralone, 4-chromanone,thiochroman-4-one and 4,4'-dimethoxybenzophenone, etc., or else they caneasily be synthesized by those skilled in the art starting from commonchemical reagents and using conventional methods of organic synthesisalready described in the literature. As previously indicated, thecarboxylic acid final products of structural formula III are, for themost part, known phenylacetic acids many of which are commerciallyavailable.

The chemical bases which are used as reagents in this invention toprepare the aforementioned pharmaceutically acceptable base salts arethose which form non-toxic salts with the various herein describedcarboxylic acid compounds, such as6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, forexample. These particular non-toxic base salts are of such a nature thattheir cations are said to be essentially non-toxic in character over thewide range of dosage administered. Examples of such cations includethose of sodium, potassium, calcium and magnesium, etc. These salts caneasily be prepared by simply treating the aforementioned carboxylicacids with an aqueous solution of the desired pharmacologicallyacceptable cation, and then evaporating the resulting solution todryness while preferably being placed under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the said acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents must be employed in order to ensure completenessof reaction and maximum production of yields with respect to the desiredfinal product.

As previously indicated, the carboxylic acid compounds of this inventionare all readily adapted to therapeutic use as oral hypoglycemic agents,in view of their ability to lower the blood sugar levels of bothdiabetic and non-diabetic subjects to a substantially significantdegree. For instance,6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, a typical andpreferred agent of the present invention, has been found to consistentlylower blood sugar levels in the fasted, glucose-loaded rat to astatistically significant degree when given by the intraperitoneal routeof administration at a dose level of 100 mg./kg. without showing anysubstantial signs of toxic side effects. The other compounds of thisinvention can also be administered in this manner without causing anysignificant untoward pharmacological side reactions. In general, thesecompounds are ordinarily administered at dosage levels ranging fromabout 0.2 mg. to about 25 mg. per kg. of body weight per day, althoughvariations will necessarily occur depending upon the condition andindividual response of the subject being treated and the particular typeof oral pharmaceutical formulation chosen.

The carboxylic acid compounds of this invention may be administeredeither alone or in combination with pharmaceutically acceptable carriersand such administration can be carried out in both single and multipledosages. More particularly, the compounds of the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe forms of tablets, capsules, lozenges, troches, hard candies,powders, aqueous suspension, elixirs, syrups and the like. Such carriersinclude solid diluents or fillers, sterile aqueous media and variousnon-toxic organic solvents, etc. Moreover, such oral pharmaceuticalcompositions can be suitably sweetened and/or flavored by means ofvarious agents of the type commonly employed for just such a purpose. Ingeneral, the therapeutically-effective compounds of this invention arepresent in such dosage forms at concentration levels ranging from about0.5% to about 90% by weight of the total composition, i.e., in amountswhich are sufficient to provide the desired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, gelatin and acacia. Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc areoften very useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includethe high molecular weight polyethylene glycols. When aqueous suspensionsand/or elixirs are desired for oral administration, the essential activeingredient therein may be combined with various sweetening or flavoringagents, coloring matter or dyes and, if so desired, emulsifying and/orsuspending agents as well, together with such diluents as water,ethanol, propylene glycol, glycerin and various like combinationsthereof.

The activity of the compounds of the present invention, as hypoglycemicagents, is determined by their ability to lower blood sugar levels inthe fasted rat when tested therein for such purposes according to theprocedure described by W. S. Hoffman, as reported in the Journal ofBiological Chemistry, Vol. 120, p. 51 (1937). The latter method measuresdirectly the amount of glucose in the blood at any given time and fromthis, the maximum percent decrease in blood sugar can be readilycalculated. In this way, the present carboxylic acid final products areshown to markedly reduce the blood sugar levels of non-anesthetized,glucose-loaded rats when administered to them at dose levels as low as100 mg./kg.

PREPARATION A

To a single-neck, round-bottomed reaction flask equipped with a magneticstirrer, a 50 ml. pressure equalizing addition funnel and anitrogen-inlet tube, there were added 10.0 g. (0.0567 mole) of6-methoxy-1-tetralone (available from the Aldrich Chemical Company,Inc., Milwaukee, Wis.) and 0.35 g. of anhydrous zinc iodide. Theaddition funnel was then charged with 19.0 g. (0.191 mole) oftrimethylsilyl cyanide and the reaction apparatus flushed with drynitrogen. Vigorous stirring of the reaction mixture then commenced,while the trimethylsilyl cyanide was added over a period of five minutescausing a modest exotherm. The resulting warm mixture was next stirredunder a dry nitrogen atmosphere for a period of 48 hours at ambienttemperatures. Work-up of the spent mixture was then achieved by dilutionof same with 300 ml. of chloroform, followed by washing of the organiclayer (three times) with saturated aqueous sodium bicarbonate. Afterremoval of the drying agent by means of filtration and the organicsolvent by means of evaporation under reduced pressure, there werefinally obtained 13 g. (83%) of pure6-methoxy-1-cyano-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene,m.p. 66°-67° C. after recrystallization from n-hexane. The yield ofanalytically pure material (m.p. 66°-67° C.) amounted to 10.0 g. (64%).

Anal. Calcd. for C₁₅ H₂₁ O₂ Si: C, 65.41; H, 7.68; N, 5.08. Found: C,65.61; H, 7.68; N, 5.46.

To a 250 ml. single-neck, round-bottomed reaction flask equipped with amagnetic stirrer, reflux condenser and nitrogen-inlet tube, there wereadded 6.0 g. (0.02179 mole) of6-methoxy-1-cyano-1-trimethylsilyloxy-1,2,3,4-tetrahydronaphthalene,followed by the addition of 20.0 g. (0.0886 mole) of stannous chloridedihydrate in one portion and then 20 ml. of glacial acetic acid and 20ml. of concentrated hydrochloric acid shortly thereafter. The reactionapparatus was then immediately flushed with dry nitrogen and plungedinto a preheated oil bath at 140° C. Vigorous stirring of the reactionmixture was then maintained, while it was slowly heated at the refluxpoint for a period of 65 hours. The resulting mixture was then cooled toroom temperature (˜25° C.), diluted with 250 ml. of chloroform and theseparated organic layer subsequently removed therefrom. The remainingaqueous phase was again saturated with chloroform and the combinedorganic layers thereafter extracted with three-75 ml. portions of 2 Naqueous potassium hydroxide, followed by back extraction of theresulting combined aqueous layers with one-75 ml. portion of diethylether. The basic aqueous layer which separated was then saved andsubsequently acidified with concentrated hydrochloric acid (with the aidof icebath cooling), followed by extraction of the acidified mixturewith three-separate 250 ml. portions of chloroform. The combinedchloroform extracts were then dried over anhydrous magnesium sulfate andfiltered, and the resulting clear filtrate was thereafter concentratedin vacuo to ultimately afford pure6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid as acrystalline residue. The yield of pure material amounted to 3.017 g.(67%). Kugelrohr distillation at 110°-180° C./0.5 mm. Hg then gaveanalytically pure product. In this way, there were finally obtained 2.91g. (65%) of analytically pure6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, m.p. 88°-89°C. [literature m.p. 96°-97° C., according to C. C. Price et al., in theJournal of the American Chemical Society, Vol. 69, p. 2261 (1977)].

Anal. Calcd. for C₁₂ H₁₄ O₃ : C, 69.88; H, 6.84. Found: C, 69.82; H,6.73.

PREPARATION B

The two-step procedure described in Preparation A was repeated exceptthat 1-tetralone (available from the Aldrich Chemical Company, Inc.,Milwaukee, Wis.) was the ultimate starting material employed in place of6-methoxy-1-tetralone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, m.p. 82°-83° C.[literature m.p. 84°-86° C., according to R. W. Kay et al., in theJournal of the Chemical Society, Vol. 105, p. 1571 (1914)]. The yield ofpure product was 68% of the theoretical value.

Anal. Calcd. for C₁₁ H₁₂ O₂ : C, 74.98; H, 6.86. Found: C, 74.77; H,6.91.

PREPARATION C

The two-step procedure described in Preparation A was repeated exceptthat 4-methyl-1-tetralone (available from the Aldrich Chemical Company,Inc., Milkaukee, Wis.) was the ultimate starting material employed inplace of 6-methoxy-1-tetralone, using the same molar proportions asbefore. In this particular case, the corresponding final productobtained was 4-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid [aviscous oil, first reported in Chemical Abstracts, Vol. 67, p. 63169R(1966)]. The yield of pure product was 58% of the theoretical value.

Anal. Calcd. for C₁₂ H₁₄ O₂ : C, 75.76; H, 7.42. Found: C, 75.71; H,7.34.

PREPARATION D

The two-step procedure described in Preparation A was repeated exceptthat 4-chromanone (available from the Aldrich Chemical Company, Inc.,Milwaukee, Wis.) was the ultimate starting material employed in place of6-methoxy-1-tetralone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained waschroman-4-carboxylic acid, m.p. 90°-91.5° C. [literature m.p. 66° C.,according to G. Fontaine in Annales de chimie, Vol. 3, p. 179 (1968)].The yield of pure product was 77% of the theoretical value.

Anal. Calcd. for C₁₀ H₁₀ O₃ : C, 67.40; H, 5.66. Found: C, 67.37; H,5.55.

PREPARATION E

6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid was preparedaccording to the procedure described by Jacques et al., in the Bulletinde la Societe chimique de France, p. 512 (1950), starting from readilyavailable materials. The product obtained was identical in every respectwith the prior art compound.

PREPARATION F

p-Chlorophenylacetic acid is commercially available and was obtainedfrom the Aldrich Chemical Company, Inc. of Milwaukee, Wis.

PREPARATION G

o-Methylphenylacetic acid is commercially available and was obtainedfrom Pfaltz & Bauer, Inc. of Stamford, Conn.

PREPARATION H

o-Methoxyphenylacetic acid is commercially available and was obtainedfrom the Distillation Products Industries division of the Eastman KodakCompany of Rochester, N.Y.

PREPARATION I

p-Methoxyphenylacetic acid is commercially available and was obtainedfrom the Distillation Products Industries division of the Eastman KodakCompany of Rochester, N.Y.

EXAMPLE 1

The two-step procedure described in Preparation A was repeated exceptthat 5-methoxy-1-tetralone (available from the Aldrich Chemical Company,Inc., Milwaukee, Wis.) was the ultimate starting material employed inplace of 6-methoxy-1-tetralone, using the same molar proportions asbefore. In this particular case, the corresponding final productobtained was 5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid,m.p. 96°-97° C. The yield of pure product was 39% of the theoreticalvalue.

Anal. Calcd. for C₁₂ H₁₄ O₃ : C, 69.88; H, 6.84. Found: C, 70.08; H,6.72.

EXAMPLE 2

The two-step procedure described in Preparation A was repeated exceptthat 6,7-dimethyl-4-chromanone [Chemical Abstracts, Vol. 58, p. 13900c(1964)] was the ultimate starting material employed in place of6-methoxy-1-tetralone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained was6,7-dimethylchroman-4-carboxylic acid, m.p. 154°-155° C. afterrecrystallization from cyclohexane. The yield of pure product was 92% ofthe theoretical value.

Anal. Calcd. for C₁₂ H₁₄ O₃ : C, 69.88; H, 6.84. Found: C, 69.89; H,6.87.

EXAMPLE 3

The two-step procedure described in Preparation A was repeated exceptthat 7-methoxy-4-chromanone (British Pat. No. 1,024,645) was theultimate starting material employed in place of 6-methoxy-1-tetralone,using the same molar proportions as before. In this particular case, thecorresponding final product obtained was 7-methoxychroman-4-carboxylicacid, m.p. 64°-67° C. The yield of pure product was 35% of thetheoretical value.

Anal. Calcd. for C₁₁ H₁₂ O₄ : C, 63.45; H, 5.81. Found: C, 63.16; H,5.73.

EXAMPLE 4

The two-step procedure described in Preparation A was repeated exceptthat thiochroman-4-one (available from Pfaltz & Bauer, Inc. of Stamford,Conn.) was the ultimate starting material employed in place of6-methoxy-1-tetralone, using the same molar proportions as before. Inthis particular case, the corresponding final product obtained wasthiochroman-4-carboxylic acid, m.p. 78°-80° C. The yield of pure productwas 71% of the theoretical value.

Anal. Calcd. for C₁₀ H₁₀ O₂ S: C, 61.83; H, 5.19. Found: C, 62.09; H,5.14.

EXAMPLE 5

The two-step procedure described in Preparation A was repeated exceptthat 4,4'-dimethoxybenzophenone (available from the Aldrich ChemicalCompany, Inc., Milwaukee, Wis.) was the ultimate starting materialemployed in place of 6-methoxy-1-tetralone, using the same molarproportions as before. In this particular case, the corresponding finalproduct obtained was α,α-di(4-methoxyphenyl)acetic acid, m.p. 110°-112°C. The yield of pure product was 24% of the theoretical value.

Anal. Calcd. for C₁₆ H₁₆ O₄ : C, 70.57; H, 5.95. Found: C, 70.45; H,5.85.

EXAMPLE 6

A mixture consisting of 5.9 g. (0.029 mole) of6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxyllic acid (prepared asdescribed in Preparation A), 100 ml. of glacial acetic acid and 100 ml.of 48% hydrobromic acid was refluxed for a period of six hours. At theend of this time, the spent reaction mixture was cooled to roomtemperature (˜25° C.) and then poured onto ice, followed by extractionof the resulting aqueous mass with ethyl acetate. After washing thelatter organic solution with water and drying over anhydrous magnesiumsulfate, the resulting clear solution was filtered and subsequentlyevaporated to near dryness while under reduced pressure to afford acrystalline mass as residue. Recrystallization of the latter materialfrom chloroform/n-hexane then gave 3.4 g. (59%) of pure6-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, m.p.133°-134° C. A second crystalline crop subsequently yielded 740 mg. ofpure material (m.p. 132°-133° C.). The pure product was furthercharacterized by means of mass spectroscopy (m/e, 192).

EXAMPLE 7

A solution consisting of 1.4 g. (0.007 mole) of6-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (prepared asdescribed in Example 6) dissolved in 35 ml. of dry tetrahydrofuran wastreated with 672 mg. of 50% sodium hydride (dispersed in mineral oil) at0° C., while under a dry nitrogen atmosphere. The resulting suspensionwas then stirred at room temperature (˜25° C.) for a period of 30minutes, followed by refluxing for a period of one hour. At this point,1.09 g. (0.007 mole) of ethyl iodide was added dropwise to the stirredmixture, followed by further refluxing for a period of 15 minutes andthen the addition of 3 ml. of dimethylsulfoxide. The resulting reactionsolution was then refluxed for a period of two hours and finally allowedto cool to room temperature. The spent reaction mixture was next stirredat room temperature and thereafter was immediately treated with 10 ml.of water in a dropwise fashion, followed by the addition of furtherwater to form a diluted aqueous system. The latter system was thenextracted with ethyl acetate and the resulting organic layer separated,while the resulting aqueous phase was saved and subsequently adjusted topH 4.5 with 6 N hydrochloric acid. The acidified aqueous system was nextextracted with ethyl acetate, and the resulting organic layers werecombined and subsequently washed well with water and dried overanhydrous sodium sulfate. After removal of the drying agent by means offiltration and the solvent by means of evaporation under reducedpressure, there was obtained a residue which was subsequentlychromatographed on silica gel using chloroform/methanol (9:1 by volume)as the eluant. Recrystallization of the major fraction from n-hexanethen gave 750 mg. (49%) of pure6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, m.p. 109°-111°C.

Anal. Calcd. for C₁₃ H₁₆ O₃ : C, 70.89; H, 7.32. Found: C, 70.99; H,7.38.

EXAMPLE 8

The procedure described in Example 7 was repeated except that benzylbromide was the alkylating agent of choice employed instead of ethyliodide, using the same molar proportions as before. In this particularcase, the corresponding final product obtained was6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, m.p.88°-92° C. The yield of pure product was 46% of the theoretical value.

Anal. Calcd. for C₁₈ H₁₈ O₃ : C, 76.57; H, 6.43. Found: C, 76.32; H,6.38.

EXAMPLE 9

The following carboxylic acid compounds are prepared by employing theprocedures previously described in Examples 1-8 (as well as PreparationsA-D), starting from readily available materials in each instance:

5-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

6-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

7-(n-butyl)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

5-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

6-(n-butoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

6,7-diethyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

6-(β-phenylethoxy)-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

4-methyl-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

6-benzyloxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

4-methyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

4-methyl-6-benzyloxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid

6-methoxychroman-4-carboxylic acid

6,8-dimethylchroman-4-carboxylic acid

6-(n-butyl)chroman-4-carboxylic acid

7-methylchroman-4-carboxylic acid

7-hydroxychroman-4-carboxylic acid

7-(n-butoxy)chroman-4-carboxylic acid

7-benzyloxychroman-4-carboxylic acid

6,8-di(n-butyl)chroman-4-carboxylic acid

7-methoxythiochroman-4-carboxylic acid

7-hydroxythiochroman-4-carboxylic acid

7-benzyloxythiochroman-4-carboxylic acid

6-methylthiochroman-4-carboxylic acid

7-(n-butyl)thiochroman-4-carboxylic acid

7-(n-butoxy)thiochroman-4-carboxylic acid

6-methoxythiochroman-4-carboxylic acid

6,7-dimethylthiochroman-4-carboxylic acid

6,8-di(n-butyl)thiochroman-4-carboxylic acid

7-(β-phenylethoxy)thiochroman-4-carboxylic acid

α,α-di(2-fluorophenyl)acetic acid

α,α-di(4-chlorophenyl)acetic acid

α,α-di(3-chlorophenyl)acetic acid

α,α-di(3-bromophenyl)acetic acid

α,α-di(2-methylphenyl)acetic acid

α,α-di(4-isobutylphenyl)acetic acid

α,α-di(3-ethoxyphenyl)acetic acid

α,α-di(4-hydroxyphenyl)acetic acid

α,α-di(4-isopropoxyphenyl)acetic acid

α,α-di(4-benzyloxyphenyl)acetic acid

EXAMPLE 10

A solution consisting of 2.82 g. (0.01 mole) of pure6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (preparedaccording to the procedure described in Example 8) dissolved in 100 ml.of ethanol is saturated with dry hydrogen chloride gas, and theresultant mixture is then refluxed for a period of approximately fourhours. Upon completion of this step, the solvent is removed by means ofevaporation under reduced pressure and the residue subsequently makealkaline by the addition thereto of a saturated aqueous sodiumbicarbonate solution. The resulting solution is then extracted withdiethyl ether, and the combined ethereal extracts are subsequently driedover anhydrous sodium sulfate and filtered. After removal of the dryingagent by means of filtration and the solvent in the usual manner, thereis obtained crude ester product in the form of a solid crystallineresidue. Recrystallization of the latter material from ethanol thenaffords the pure ethyl ester of6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid insubstantial yield.

EXAMPLE 11

The procedure described in Example 10 is repeated except for the factthat methanol is the reagent employed instead of ethanol and the methylester of 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid isthe corresponding final product thus obtained.

In like manner, the n-propyl, isopropyl, n-butyl, isobutyl, n-amyl,isoamyl and n-hexyl esters of6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid are alsosimilarly prepared by merely employing the appropriate alcohol of choicein place of ethanol in each particular case.

EXAMPLE 12

The procedure described in Example 10 is repeated except that7-methoxychroman-4-carboxylic acid (prepared according to the proceduredescribed in Example 3) is the starting material employed in place of6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid for thepresent purposes at hand. In this particular case, the correspondingfinal product thus obtained is the ethyl ester of7-methoxychroman-4-carboxylic acid.

In like manner, the methyl, n-propyl, isopropyl, n-butyl, isobutyl,n-amyl, isoamyl and n-hexyl esters of 7-methoxychroman-4-carboxylic acidare also each similarly prepared, as are the corresponding lower alkylesters of the other carboxylic acids of this invention which arereported in Examples 1-2, 4-7 and 9, respectively.

EXAMPLE 13

A mixture of 1.41 g. (0.005 mole) of6-benzyloxy-1,2,3,4-tetrahydro-1,2,3,4-naphthalene-1-carboxylic acid and10 ml. of thionyl chloride dissolved in 300 ml. of chloroform isrefluxed for a period of approximately 2.5-4 hours. After cooling toroom temperature (˜25° C.), the reaction mixture is slowly poured into asolution consisting of 4.5 g. of sodium hydroxide dissolved in 100 ml.of ammonium hydroxide. The resulting chloroform layer is then separatedand subsequently evaporated to near dryness while under reduced pressureto give a residual solid. Recrystallization of the latter material fromethanol-water then yields pure6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide in finecrystalline form.

EXAMPLE 14

The procedure described in Example 13 is repeated except that7-methoxychroman-4-carboxylic acid is the starting material employed inplace of 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid forthe present purposes at hand. In this particular case, the correspondingfinal product thus obtained is 7-methoxy-chroman-4-carboxamide.

In like manner, the unsubstituted amides of the other carboxylic acidsof this invention are also similarly prepared by merely employing theappropriate acid starting material of choice (taken from Examples 1-2,4-7 and 9, respectively) in each particular case.

EXAMPLE 15

The sodium salt of6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid is preparedby dissolving said acid in water containing an equivalent amount inmoles of sodium hydroxide and then freeze-drying the mixture. In thisway, the desired alkali metal salt of the carboxylic acid is obtained inthe form of an amorphous powder which is freely-soluble in water.

In like manner, the potassium and lithium salts are also similarlyprepared, as are the other alkali metal salts of all the othercarboxylic acids of this invention which are reported in Examples 1-7and 9, respectively.

EXAMPLE 16

The calcium salt of 7-methoxychroman-4-carboxylic acid is prepared bydissolving said acid in water containing an equivalent amount in molesof calcium hydroxide and then freeze-drying the mixture. Thecorresponding magnesium salt is also prepared in this manner, as are allthe other alkaline-earth metal salts not only of this particularcompound, but also of those carboxylic acids previously described inExamples 1-2 and 4-9, respectively.

EXAMPLE 17

A dry solid pharmaceutical composition is prepared by blending thefollowing materials together in the proportions by weight specifiedbelow:

    ______________________________________                                        6-Benzyloxy-1,2,3,4-tetrahydronaphthalene-                                    1-carboxylic acid        50                                                   Sodium citrate           25                                                   Alginic acid             10                                                   Polyvinylpyrrolidone     10                                                   Magnesium stearate       5                                                    ______________________________________                                    

After the dried composition is thoroughly blended, tablets are punchedfrom the resulting mixture, each tablet being of such size that itcontains 200 mg. of the active ingredient. Other tablets are alsoprepared in a similar fashion containing 25, 50 and 100 mg. of theaction ingredient, respectively, by merely using the appropriate amountof the carboxylic acid compound in each case.

EXAMPLE 18

A dry solid pharmaceutical composition is prepared by combining thefollowing materials together in the proportions by weight indicatedbelow:

    ______________________________________                                        α,α-Di(4-methoxyphenyl)acetic acid                                                        50                                                    Calcium carbonate       20                                                    Polyethylene glycol, average molecular                                        weight 4000             30                                                    ______________________________________                                    

The dried weight solid mixture so prepared is then thoroughly agitatedso as to obtain a powdered product that is completely uniform in everyrespect. Soft elastic and hard-filled gelatin capsules containing thispharmaceutical composition are then prepared, employing a sufficientquantity of material in each instance so as to provide each capsule with250 mg. of the active ingredient.

EXAMPLE 19

The following carboxylic acid final products of Preparations A-I andExamples 3-5 and 7-8, respectively, were tested for hypoglycemicactivity in terms of their ability to exhibit improved glucose tolerancein groups of five or six male albino rats (each weighing approximately200-255 g.) of the Charles River strain. No anesthetic was used in thisstudy. The rats were fasted for approximately 18-24 hours prior toadministration, a blood sample (zero time) was taken from the tail veinof each animal (having cut at a point just 2 mm. from the tip of thetail) and each animal so examined was thereafter treated with glucose ata dose level of 1.0 g./kg. (made up in 0.9% saline), via theintraperitoneal route of administration, followed by treatment witheither saline alone (controls) or the test compound to be administeredat a dose level of 100 mg./kg., also by the intraperitoneal route ofadministration. Additional blood samples were then taken from the tailvein in the same manner as before at 0.5, 1, 2 and 3 hour intervalsafter administration of the drug. The samples were immediately diluted1:10 (by volume) with 0.1% heparin in 0.9% saline. Blood glucoseconcentrations (mg./dl.) were then determined by adapting the method ofW. S. Hoffman [Journal of Biological Chemistry, Vol. 120, p. 51 (1937)]to the Autoanalyzer instrument produced by Technicon InstrumentsCorporation of Chauncey, N.Y. On this basis, the maximum percentdecrease in blood glucose was calculated and reported as such (i.e., ashypoglycemic activity in terms of improved glucose tolerance) for thevarious compounds listed in the table below:

    ______________________________________                                                          Max. % Decrease                                             Compound          Blood Glucose                                               ______________________________________                                        Product of Preparation A                                                                        17                                                          Product of Preparation B                                                                        12                                                          Product of Preparation C                                                                        16                                                          Product of Preparation D                                                                        18                                                          Product of Preparation E                                                                        13                                                          Product of Preparation F                                                                        25                                                          Product of Preparation G                                                                        20                                                          Product of Preparation H                                                                        27                                                          Product of Preparation I                                                                        32                                                          Product of Example 1                                                                            15                                                          Product of Example 2                                                                            14                                                          Product of Example 3                                                                            11                                                          Product of Example 4                                                                            15                                                          Product of Example 5                                                                            18                                                          Product of Example 7                                                                            22                                                          Product of Example 8                                                                            18                                                          ______________________________________                                    

I claim:
 1. A pharmaceutical composition suitable for oraladministration comprising a pharmaceutically acceptable carrier and aneffective blood sugar lowering amount of an oral hypoglycemic agent,said agent being a compound selected from the group consisting ofcarboxylic acids of the formula: ##STR6## and the lower alkyl esters andunsubstituted amide derivatives thereof, and the base salts of saidacids with pharmacologically acceptable cations, whereinW is --CH₂ -- or--CH(CH₃)--; X is hydrogen or lower alkyl; and X¹ is hydrogen, loweralkyl, lower alkoxy or lower phenylalkoxy, with the proviso that when X¹is other than lower alkyl, X is hydrogen.
 2. The composition as claimedin claim 1 wherein X and X¹ are each hydrogen and W is --CH₂ --.
 3. Thecomposition as claimed in claim 1 wherein X is hydrogen, X¹ is loweralkoxy and W is --CH₂ --.
 4. The composition as claimed in claim 1wherein X is hydrogen, X¹ is lower phenylalkoxy and W is --CH₂ --. 5.The composition as claimed in claim 1 wherein X and X¹ are each hydrogenand W is --CH(CH₃)--.
 6. The composition as claimed in claim 3 whereinthe hypoglycemic agent is6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.
 7. Thecomposition as claimed in claim 3 wherein the hypoglycemic agent is6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid.
 8. Thecomposition as claimed in claim 3 wherein the hypoglycemic agent is6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.
 9. Thecomposition as claimed in claim 4 wherein the hypoglycemic agent is6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.
 10. Amethod for lowering blood sugar in the treatment of a diabetic host,which comprises orally administering to said host an effective bloodsugar lowering amount of a compound selected from the group consistingof carboxylic acids of the formula: ##STR7## and the lower alkyl estersand unsubstituted amide derivatives thereof, and the base salts of saidacids with pharmacologically acceptable cations, whereinW is --CH₂ -- or--CH(CH₃)--; X is hydrogen or lower alkyl; and X¹ is hydrogen, loweralkyl, lower alkoxy or lower phenylalkoxy, with the proviso that when X¹is other than lower alkyl, X is hydrogen.
 11. The method as claimed inclaim 10 wherein the compound administered is4-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.
 12. The methodas claimed in claim 10 wherein the compound administered is6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.
 13. Themethod as claimed in claim 10 wherein the compound administered is6-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.
 14. The methodas claimed in claim 10 wherein the compound administered is6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid.